Ethanol-induced locomotor sensitization in DBA/2J mice is associated with alterations in GABAA subunit gene expression and behavioral sensitivity to GABAA acting drugs

Abstract

Repeated exposure to ethanol may produce increased sensitivity to its acute locomotor stimulant actions, a process referred to as locomotor sensitization. Neuroadaptation within certain brain circuits, including those possessing GABAA receptors, may underlie locomotor sensitization to ethanol. Indeed, GABAA receptors are documented mediators of ethanol's cellular and behavioral actions. Moreover, because subunit composition of this receptor is predictive of its pharmacology, it is possible that alterations in subunit composition contribute to the expression of locomotor sensitization to ethanol. The goal of the present study was to determine if alterations in GABAA subunit composition are associated with the expression of locomotor sensitization in DBA/2J mice, a strain known to be particularly susceptible to the development of this behavioral phenomenon. Following a modified 14 day sensitization procedure (Phillips et al., 1994) relative changes in GABAA subunit gene expression were assessed in discrete mesolimbic brain regions. To determine if the observed changes in gene expression produced functional changes in the locomotor responses to drugs known to either preferentially or generally activate GABAA receptors normally possessing the significantly altered subunits, separate cohorts of animals were challenged with one of several low doses of zolpidem (α1-selective), etomidate (β2/3-selective), or flurazepam (γ2-directed) and assessed for locomotor alterations. Sensitized animals displayed increased expression of the α1, β2, and γ2 (v1) subunits in the Nucleus Accumbens (NAc) but not Ventral Tegmental Area (VTA). Additionally, sensitized animals displayed altered sensitivity to the locomotor actions of etomidate and flurazepam. These results support the hypothesis that neuroadaptive changes in GABAA subunit composition participate in the expression of locomotor sensitization.

Differential effects of context on psychomotor sensitization to ethanol and cocaine

“…For example, we have shown similar levels of ethanol sensitization between mice injected repeatedly with ethanol in the test context or in their home cages (Didone et al, 2008). It is also noteworthy that the standard experimental protocol used to study ethanol sensitization in several laboratories involves the repeated administration of ethanol in the home cage and a test session in a different environment (Quadros et al, 2002;Meyer and Phillips, 2007;Linsenbardt and Boehm, 2010). Although these latter studies were not aimed at testing the context dependency of ethanol sensitization, it is clear from their results that the development of a robust ethanol sensitization does not require association with a specific context.…”

Activation of extrasynaptic δ-GABAA receptors globally or within the posterior-VTA has estrous-dependent effects on consumption of alcohol and estrous-independent effects on locomotion

“…Quanitative real-time reverse transcriptase PCR (qPCR) was performed to compare mRNA levels of three GABA A receptor subunits, as previously described (Linsenbardt and Boehm, 2010), across the estrous cycle. The δ and α4 subunits are exclusively expressed by extrasynaptic GABA A receptors, whereas ɣ2 is often found in synaptic GABA A receptors.…”

Blockade of Ethanol-Induced Behavioral Sensitization by Sodium Butyrate: Descriptive Analysis of Gene Regulations in the Striatum

“…For instance, it has been demonstrated that the expression of homer 1A, dopamine D3 receptor, several GABA receptor subunits genes, and immediate early genes such as egr-1 and c-Fos is altered after EIBS (Faria et al, 2008;Harrison and Nobrega, 2009;Linsenbardt and Boehm, 2010;dos Santos et al, 2009). Thus we sought to carry out an exploratory analysis to identify regulations of expression from genes belonging to signal transduction-and epigeneticrelated pathways.…”